Organic bromides are stable organic compounds, which are used commercially for many applications, such as pharmaceuticals, agriculture, disinfectants, flame extinguishing agents, and dyes. Organic bromides have found wide use in numerous industrial applications as chemical intermediates for the production of other commercial organic compounds (Ullmann's Encyclopedia of Industrial Chemistry 2012, v. 6, 331-358; v. 8, 483-519).
Reaction of benzoic acid with tribromoisocyanuric acid (TBCA) in trifluoroacetic acid gave only 3-bromobenzoic acid—the product of electrophilic bromination of aromatic C—H bond (Synlett 2013 v. 24, 603-605).
Organic carboxylic acids are widely available and cheap raw materials in organic synthesis. Therefore, the oxidative decarboxylation of organic carboxylic acids with concomitant replacement by bromine (bromodecarboxylation) is an extremely useful method for regioselective synthesis of organic bromides.
The Hunsdiecker reaction (Tetrahedron 1971, v. 27, 5323) is a bromodecarboxylation reaction, which utilizes the treatment of anhydrous silver salt of organic acid with molecular bromine in an inert solvent. This reaction, however, is extremely sensitive to presence of trace amounts of water, which lead to the recovery of unreacted acid. Another way to perform the Hunsdiecker reaction is by using a mixture of organic carboxylic acid and Br2/HgO (J. Org. Chem. 1965, v. 30, 415) instead of the silver salt.
Accordingly, the Hunsdiecker reaction and/or its modifications use heavy metal salts such as those of silver and mercury, therefore the disadvantages of such procedures for the pharmaceutical industry are obvious.
The Barton halo-de-carboxylation procedure (Barton et al., Tetrahedron 1985, v. 41, 3901; 1987, v. 43, 4321) is directed to the conversion of organic carboxylic acids to the esters of N-hydroxypyridine-2-thione. The thiohydroxamic esters are brominated by BrCCl3. Thiopyridines are formed in the reaction as co-products.
Additional process for converting organic carboxylic acids to their corresponding bromides is by treating the carboxylic acid with (diacetoxyiodo)benzene and bromine or LiBr as bromine source (Tetrahedron 2000, v. 56, 2703; Synlett 2011, 1563). However, in this reaction, it is difficult to separate the desired product from iodobenzene, which is formed as co-product in the reaction.
A bromodecarboxylation of aromatic carboxylic acids using CuBr2 as the halogen sources has been developed by Wu et. al. (Tetrahedron Letters 2010, v. 51, 6646) and Liu et. al. (Tetrahedron Letters 2013, v. 54, 3079), which also utilize the use of heavy metals in their reactions.
Another example for bromodecarboxylation utilizes the reagent system 1205-KBr for bromodecarboxylation of electron-rich arenecarboxylic acids (Synlett 2014, v. 25, 2508). This method, however, is limited to preparation of specific brominated phenol ether derivatives.
N-Bromoamides such as N-bromosuccinimide (Chem. Pharm. Bull. 2002, v. 50, 941), 1,3-dibromo-5,5-dimethylhydantoin (Bioorg. Med. Chem. 2008, v. 16, 10001; Bioorg. Med. Chem. Lett. 2011, v. 21, 3227; Tetrahedron 2014, v. 70, 318), dibromoisocyanuric acid (Monatsh. Chem. 1968, v. 99, 815; 1969, v. 100, 42 & 1977, v. 108, 1067), tribromoisocyanuric acid (Synlett 2013, v. 24, 603), are useful reagents for the electrophilic bromination of aromatic carboxylic acids in the meta-position with respect to the carboxylic group. However, the use of these reagents in bromo-decarboxylation reactions is rather limited.
For example, reaction of N-bromosuccinimide with arenecarboxylic acids, predominantly electron-rich arenecarboxylic acids, yields bromoarenes (IN803DEL1999; JOC 2009, v. 74, 8874; Tetrahedron Lett. 2007, v. 48, 5429). Reaction of 3-aryl acrylic and propiolic acids with N-bromosuccinimides (J. Org. Chem. 2002, v. 67, 7861) and tribromoisocyanuric acid (J. Braz. Chem. Soc. 2013, v. 24, 213) yields 2-bromovinyl and 2-bromoethynyl arenes. All of these reactions are heterolytic reactions that do not require initiation with radical initiators or UV-visible light irradiation.
The conversion of carboxylic acid R—CO2H, to their corresponding bromide, R—Br, is therefore a rather difficult transformation. There is a need for the development of new strategies for bromodecarboxylation.